Scientific Notation:

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Abstract:

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder caused by a lack of paternal gene expression from 15q11–q13 and is characterized by a failure to thrive in infancy, followed by impaired skeletal growth, hyperghrelinemia, reduced satiety responses, hyperphagia and obesity. We have shown that many of these characteristics are replicated in a mouse model for this condition in which the imprinting center of the homologous PWS interval has been deleted (PWS-IC mice). However, despite hyperghrelinemia, proportionate hyperphagia and exaggerated food hoarding behavior, these animals remain remarkably lean, abdominal white adipose tissue (WAT) depots being reduced by 70-80% (1). Since circulating lipids are regulated in rodents by the activity of brown adipose tissue (BAT) (2), we have now investigated whether leanness in PWS-IC mice arises from dysregulated thermogenesis.

When maintained in standard housing conditions, interscapular BAT weight in PWS-IC mice was 48% lower than in wild-type (WT) mice (p<0.01), brown adipocytes showing reduced lipid storage. Since this suggested increased lipid utilization, we used thermal imaging to reveal that the surface temperature of PWS-IC mice was increased by 1.4 and 2.0°C in the head and interscapular regions (p<0.05), while lumbar and tail root temperatures were unaffected. In order to determine whether this elevated thermogenesis could be corrected by maintaining PWS-IC mice in thermoneutral conditions, 6 month-old WT and PWS-IC mice were maintained at room temperature (RT; 20-22°C) or thermoneutrality (TN; 30°C) for 9 weeks. In WT mice daily food intake was unaffected at TN, with mean terminal body weight and proportionate inguinal, retroperitoneal and omental WAT mass being 150, 115, 139 and 175% of that in RT-maintained mice. Proportionate interscapular BAT mass in WT mice at TN was 119% of that in RT-maintained mice, with clear evidence of lipid engorgement in brown adipocytes. In contrast, daily food intake was reduced by 38% in TN-maintained PWS-IC mice (p<0.01), with body weight gain reversed from 0.86±0.30g (RT) to -1.80±1.30g (p<0.05) in TN-maintained mice. In addition, the proportionate mass of the inguinal, retroperitoneal and omental depots in TN-maintained PWS-IC mice was 82, 94 and 131% of that in RT-maintained PWS mice. Although proportionate BAT mass was unaltered in TN-maintained PWS-IC mice, lipid storage appeared increased.

Thus, although overactive BAT and excess thermogenesis may contribute to the development of abdominal leanness in PWS-IC mice, the effect of suppressing BAT function on WAT mass is obscured by reduced food intake. Given the sporadic reports of hyperthermia in human PWS infants (3,4), it is now important to establish the relationship between BAT activity, food intake and WAT mass in children with this condition and determine whether activation of BAT could ameliorate the obesity usually seen in PWS.